Abstract
We aimed to construct a novel population pharmacokinetics (PPK) model of doripenem (DRPM) for Japanese patients in intensive care unit, incorporating the clearance of DRPM by continuous renal replacement therapy (CRRT). Twenty-one patients treated with DRPM (0.25 or 0.5 g) by intravenous infusion over 1 h were included in the study. Nine of the 21 patients were receiving CRRT. Plasma samples were obtained before and 1, 2, 4, 6 and 8 h after the first DRPM administration. PPK analysis was conducted by nonlinear mixed effects modeling using a two-compartment model. Total clearance (CLtotal) in the model was divided into CRRT clearance (CLCRRT) and body clearance (CLbody). The final model was: CLtotal (L h−1) = CLbody(non-CRRT) = 3.65 × (Ccr/62.25)0.64 in the absence of CRRT, or = CLbody(CRRT) + CLCRRT = 2.49 × (Ccr/52.75)0.42 + CLCRRT in the presence of CRRT; CLCRRT = QE × 0.919 (0.919 represents non-protein binding rate of DRPM); V1 (L) = 10.04; V2 (L) = 8.13; and Q (L h−1) = 3.53. Using this model, CLtotal was lower and the distribution volumes (V1 and V2) tended to be higher compared to previous reports. Also, Ccr was selected as a significant covariate for CLbody. Furthermore, the contribution rate of CLCRRT to CLtotal was 30–40%, suggesting the importance of drug removal by CRRT. The population analysis model used in this study is a useful tool for planning DRPM regimen and administration. Our novel model may contribute greatly to proper use of DRPM in patients requiring intensive care.
Highlights
We aimed to construct a novel population pharmacokinetics (PPK) model of doripenem (DRPM) for Japanese patients in intensive care unit, incorporating the clearance of DRPM by continuous renal replacement therapy (CRRT)
Since DRPM shows a time-dependent effect based on the pharmacokinetic and pharmacodynamics (PK/PD) theory, bactericidal effect is greater when the blood concentration is maintained above the minimum inhibitory concentration (MIC) for 40% of the time or more[5]
Plasma DRPM concentrations were measured by high performance liquid chromatography (HPLC) according to the procedures we reported p reviously[21]
Summary
We aimed to construct a novel population pharmacokinetics (PPK) model of doripenem (DRPM) for Japanese patients in intensive care unit, incorporating the clearance of DRPM by continuous renal replacement therapy (CRRT). The PPK model reported by Bhavnani et al.[6] was constructed using an intravenous 2-compartment model based on plasma DRPM concentrations obtained in a phase 1 DRPM clinical trial. In the PPK analysis reported by Nandy et al.[8], covariates such as Ccr, body weight (BW), age and race were incorporated using an intravenous 2-compartment model for a wide range of subjects in phases 1–3 trials. They reported differences in DRPM clearance depending on race. Other r eports[13,14,15] suggested that the risk of death in septic
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